N-aryl-n&#39;-cyclopropyl-ethylene diamine derivatives



United States Patent 3,365,458 N-ARYL-N-CYCLOPROPYL-ETHYLENE DIAMINE DERIVATIVES John H. Biel and Edward J. Warawa, Milwaukee, Wis.,

assiguors t0 Aldrich Chemical Company, Inc., Milwaukee, Wis., a corporation of Wisconsin No Drawing. Continuation-impart of abandoned application Ser. No. 377,387, June 23, 1964. This application May 11, 1965, Ser. No. 454,972

12 Claims. (Cl. 260294.8)

ABSTRACT OF THE DISCLOSURE N-disubstituted-N' cyclopropylethylenediamines and the pharmaceutically acceptable nontoxic salts thereof exhibit antidepressant activity and are useful as antidepressants.

The compounds are prepared by reduction of the corresponding acetamide, e.g., a-(N-benzyl-N-methynamino-N'eyclopropylacetamide to the ethylenediamine.

This application is a continuation-in-part of our prior, co-pending application Ser. No. 377,387, filed June 23, 1964.

This invention relates to novel compounds. More particularly, this invention relates to novel compounds which possess valuable therapeutic utility as antidepressants and monoamine oxidase inhibitors, and to intermediates useful in the preparation thereof. In another aspect, this invention relates to a novel method of treating depression.

It is an object of this invention to provide a new class of therapeutic compounds. It is another object of the present invention to provide novel compounds having antidepressant activity. It is a further object of the present invention to provide novel compounds which inhibit the enzyme monoamine oxidase. It is a still further object of the present invention to provide a novel method of treating depression.

These and other objects which may appear as the specification proceeds are achieved by this invention which comprises the provision of compounds selected from the group consisting of compounds having the following formula and the pharmaceutically acceptable nontoxic salts thereof. In Formula I, R is a member selected from the group consisting of (lower)alkynyl, thienyl, furyl, pyridyl, pyrrolyl, naphthyl and Ph-, wherein Ph is a radical of the formula (II) R atoms, inclusive, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;

R is a member selected from the group consisting of hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, phenylalkyl, wherein the alkyl moiety contains from 1 to 4 carbon atoms, inclusive, and phenylalkenyl, wherein the alkenyl moiety contains from 1 to 4 carbon atoms, inclusive;

R is a member selected from the group consisting of hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, Ph-, Ph-alk-, and Ph-a1ken-, in which Ph is as represented above, alk represents a divalent alkylene radical containing from 1 to 4 carbon atoms, inclusive, and alken represents a divalent alkenylene radical containing from 2 to 4 carbon atoms, inclusive; and

Y is a member selected from the group consisting of (lower)alkylene, (lower)alkenylene, (lower) alkynyl ene, oxy(lower)alkylene and mercapto(lower) alkylene. The pharmaceutically acceptable nontoxic salts include the organic and inorganic monoand diacid addition salts, e.g., those prepared from acids such as hydrochloric, sulfuric, sulfamic, tartaric, fumaric, hydrobromic, hydriodic, glycolic, citric, maleic, phosphoric, succinic, acetic, nitric and the like.

The term (lower)alkyl as used herein means both straight and branched chain alkyl radicals containing from 1 to 8 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, 2-ethylhexyl, etc.

The term (lower)alkenyl as used hereinmeans both straight and branched chain alkenyl radicals containing from 2 to 8 carbon atoms, e.g., ethenyl, allyl, l-propenyl, l-butenyl, 3-butenyl, Z-methyl-l-propenyl, 3-pentenyl, 1- hexenyl, 7-octenyl, etc.

The term (lower)alkynyl as used herein means both straight and branched chain alkynyl radicals containing from 2 to 8 carbon atoms, e.g., ethinyl, propargyl, 1- butinyl, Z-butinyl, 1,1-dimethylpropargyl, l-pentiuyl, 1- heptinyl, etc.

The term (lower) alkylene as used herein means both straight and branched chain alkylene radicals containing from 1 to 8 carbon atoms, e.g., methylene, ethylene, octylene, propylene, butylene, isobutylene, t-butylene, amylene, hexylene, 2-ethylhexylene, etc.

The term (lower) alkenylene as used herein means both straight and branched chain alkenylene radicals containing from 2 to 8 carbon atoms, e.g., ethenylene, 1-propenylene, 3-butenylene, 2-methyl-l-butenylene, etc.

The term (lower)alkynylene as used herein means both straight and branched chain alkynylene radicals containing from 2 to 8 carbon atoms, e.g., ethinylene, propargylene, l-propinylene, 3-butinylene, 1,1-dimethyl-3- butinylene, hexinylene, octinylene, etc.

Similarly, where the term (lower) is used as part of the description of another group, eg (lower)alkoxy, it refers to the alkyl portion of such group which is therefore as described in connection with (lower)alkyl.

Preferred compounds of the present invention are those having the following formulae wherein n, R R R R R and Y are as represented above.

Still more preferred compounds of the present invention are those having the following formulae wherein R R R and R are as represented above.

Preferred individual compounds of this invention are those having the formulae (XVIII) (XIX) (XXI) CH3 CH:

The compounds of this invention are valuable pharmaceutical agents. They produce marked increase in central nervous system activity which makes the compounds useful as antidepressant agents. In addition, the compounds inhibit the enzyme monoamine oxidase which makes the compounds useful as monoamine oxidase inhibitors.

It is generally accepted that elevation of certain brain amines results in psychic effects clinically. These effects take the form of mood elevation or antidepressant action.

Brain norepinephrine and serotonin are brain amines chiefly metabolized by the enzyme monoamine oxidase. Inhibitors of this enzyme produce a characteristic elevation of these brain amines; and the ability of a compound to increase the level of brain norepinephrine and serotonin is well correlated with central monoamine oxidase inhibition.

The effect of the compounds of this invention on brain norepinephrine and serotonin was determined in mice by the method of Shore et al. (J. Pharmacol. 112, 295-300, 1958), as modified by Mead et a1. (Bioch. Pharmacol. 6, 52-53, 1961), for the simultaneous extraction of both norepinephrine and serotonin from the same homogenate. The method involves extraction of norepinephrine and serotonin into butanol, return of the amines to an aqueous phase and conversion to a fiuorscent derivative. Norepinephrine was determined by oxidation at pH 5, to trihydroxyindole, and serotonin by its native fluorscence in 3 N hydrochloric acid. The brain of eight mice were pooled for each determination, and the compound was administered orally. The level of brain amines was determined at different intervals after administration, and a control group was run in each experiment.

The results for the preferred compound of the present invention, N benzyl-N-methyl-N-cyclopropylethylenediamine, are summarized in the following table and show that the compound is a potent elevator of brain amines, and is, therefore, a powerful antidepressant agent.

The compounds of this invention are also capable of preventing the sedative eiiects of reserpine in mice. Oral administration of as little as mg./ kg. of the preferred compound of the present invention, N-benZyl-N-methyl- N-cyclopropylethylenediamine, in mice three hours before intravenous administration of 5 mg./ kg. of reserpine completely prevented symptoms usually associated with reserpine administration, ie., increased motor activity, profuse salivation, and ptosis. Thus, the preferred compound of the present invention is a powerful monoamine oxidase inhibitor, and exhibits marked antidepressant activity. N-benzyl-N-methyl-N-cyclopropylethy1enediamine exhibited an oral LD in mice of 849 mg./kg.

The compounds of the present invention are prepared by the acylation of a primary or a secondary cyclopropylamine of the formula wherein R and R are as represented above with an ahaloacetylhalide or an a-tosylacetylhalide of the formula wherein X is chloro, bromo, iodo, fluoro, or tosyl, and Z is chloro, bromo, iodo, or fiuoro, in the presence of an acid acceptor such as potassium carbonate, pyridine, triethylamine or sodium hydroxide in an aqueous acetone or benzene solution to yield an N-cyelopropyl u-haloor tosylacetamide of the formula (XXVI) R wherein X, R and R are as represented above. This procedure is generally described in United States Patent No. 2,569,288.

Representative of the primary cyclopropylamines which may be used in this process are,

N-cyclopropyl-N-methylamine, N-cyclopropyl-N-isopropylamine,

N-cyclop ropyl-N-allylamine,

N-cyclopropyl-N-propargylamine,

N-cyclopropyl-N-benzylamine,

N-cyclopropyl-N-phenylis opropylamine,

N-cyclo pro pyl-N-cinnamylamine,

N-fl-phenylcyclopropyl-N-methylamine,

N-flm-trifluoromethyl phenylcyclopropyl-N- methylamine,

N-fl- (p-fluoro phenylcyclopropyl-N-allylamine,

N-fl-(m,p-methylenedioxy) phenylcyclopropyl-N- propargylamine and N-flo-methylmercapto) phenylcyclopropyl-N- benzyl amine.

Some of the a-haloor tosylacetamide halides which may be used in this process are,

a-chloroacetyl chloride, ot-bromoacctyl chloride, a-iodoacetyl bromide and a-para-tosylacetyl chloride.

Some of the N'-cyclopropyl a-haloor tosylacetamides thus formed are,

N-cyclopropyl a-chloroacetamide, N-Z-methylcyclopropyl a-bromoacetamide, N-Z-phenylcyclopropyl u-iodoacetamide, N-Z-allylcyclopropyl ot-chloroacetamide,

, N-Z-propargylcyclopropyl a-tosylacetamide,

N-2-(m-trifluoromethyl)phenylcyclopropyl u-ChlOlO- acetamide,

N-2-(p-fiuoro)phenylcyclopropyl a-bromoacetamide,

N-2-(o-bromo)phenylcyclopropyl a-chloroacetamide,

N-2-(p-ethoxy)phenylcyclopropyl a-bromoacetamide,

N-2- (in, p -methylenedioxy) phenylcyclopropyl u-chloroacetamide,

N-2- o-methylmercapto phenylcyclopropyl a-chloroacetamide,

N-cyclopropyl-N-methyl a-bromoacetamide,

N-cyclopropyl-N-isopropyl a-bromoacetamide,

N-cyclopropyl-N-benzyl a-bromoacetamide,

N-2-methylcyclopropyl-N-allyl a-bromoacetamide,

N-Z-phenyl-cyclopropyl-N-propargyl a-iodoacetamide,

N-2- (m-trifluoromethyl) phenylcyclopropyl-N-propargyl a-iodoacetamide, N-2-allylcyclopropyl-N-methyl a-bromoacetamide, N-Z-(p-fluoro phenylcyclopropyl-N-benzyl a-bromoacetamide, N-cyclopropyl-N-propargyl a-bromoacetamide, N-Z-phenylcyclopropyl-N-methyl oc-bromoacetamide, N-2-(o-chloro) phenylcyclopropyl-N-methyl a-bromoacetamide and N-2-( o-methyl) phenylcyclopropyl-N-propargyl a-bromoacetamide.

The N'-cyclopropyl a-haloor tosylacetamides are converted to N-cyclopr0pylglycina'mides of the formula (XXVII) s amine, potassium carbonate, aminopyrine, N-ethylanilin'e and an inert solvent such as benzene, toluene, Xylene, dimethylformamide, dioxane, at elevated temperatures, e.g., reflux temperature. Isolation of the desired N'-cyclopropylglycinamide is then brought about by fractional distillation or crystallization. This step is generally described in United States Patent No. 2,927,180.

Some of the primary amines which may be used in this step of the process are,

aniline, m-trifiuoromethylaniline, o-bromoaniline, o-methylaniline, p-propargyloxyaniline, p-ethoxyaniline, m-methoxyaniline, o-methylmercaptoaniline, benzylamine, a-methylbenzylamine, a-isopropylbenzylamine, o-chlorobenzylamine, p-fluorobenzylamine, m-trifiuoromethylbenzylamine, o-methylmercaptobenzylamine, p-ethoxybenzylamine, p-propargyloxybenzylamine, m,p-methylenedioxybenzylamine, p-phenoxybenzylamine, p-phenylbenzylamine, p-dialkylsulfamylbenzylamine, a-naphthylamine, fl-naphthylamine, a-naphthylmethylamine, fl-naphthylmethylamine, phenylisopropylamine, p-fluorophenylisopropylamine, m-trifluoromethylphenylisopropylamine, p-ethoxyphenylisopropylamine, c-methylmercaptophenylisopropylamine, o-methylphenylisopropylamine, a-thienylmethylamine, fl-trienylmethylamine, Z-furfurylmethylamine, 2-pyridylmethylamine,

3 -pyridylmethy1amine, 4-pyridylmethylamine, 2-pyridylethylamine, 3-pyridylethylamine, 4-pyridylethylamine, l-pyrrolylmethylamine, propargylamine,

ethinylamine and butinyl.

Some of the secondary amines which may be used in this step of the process are,

N-phenyl-N-methylamine, N-phenyl-N-propargylamine, N-phenyl-N-allylamine, N-phenyl-N-cyclopropylamine, N-phenyl-N-cyclobutylamine, N-phenyl-N-cyclopentylamine, N-benzyl-N-methylamine, N-benzyl-N-allylamine, N-benzyl-N-propargylamine, N-benzyl-N-cyclopropylamine, N-benzyl-N-cyclobutylamine, N-benzyl-N-cyclopentylamine, N-benzyl-N-cycloheptylamine, N-benzyl-N-cyclooctylamine, N-p-ethoxyphenyl-N-methylamine, N-p-ehlorophenyl-N-methylamine, N-o-bromophenyl-N-methylamine, N m-trifluoromethylphenyl-N-methylamine, N-3 ,4-methy1enedioxyphenyl-N-methylamine, N-o-methylmercaptophenyl-N-methylamine, N-p-dialkylsulfamylphenyl-N-methylamine, N-o-methylphenyl-N-methylamine, N-o-met'hylbenzyl-N-methylamine, N-o-bromobenzyl-N-methylamine,

8 N-p-fiuorobenzyl-N-methylamine, N-rn-trifiuoromethylbenzyl-N-methylamine, N-p-ethoxybenzyl-N-methylamine, N-p-propargyloxybenzyl-N-methylamine, N-p-phenoxybenzyl-N-methylamie, N-p-phenylbenzyl-N-methylamine, N-3,4-methylenedioXybenzyl-N-methylamine, N-0-methylmercaptobenzyl-N-methylamine, N-p-dialkylsulfamylbenzyl-N-methylamine, N-o-methylbenzyl-N-propargylamine, N-o-brornobenzyl-N-propargylamine, N-p-fluorobenzyl-N-propargylamine, N-m-trifiuorornethylbenzyl-N-propargylamine, N-p-ethoxybenzyl-N-propargylamine, N-p-propargyloxybenzyl-N-propargylamine, N-p-phenoxybenzyl-N-propargylamine, N-p-phenylbenZyl-N-propargylamine,

N-3 ,4-methylenedioxybenzyl-N-propargylamine, N-o-methylmercaptobenzyl-N-propargylamine, N-p-dialkylsulfamylbenzyl-N-propargylamine, N-methyl-N-propargylamine, N-ethyl-N-proparg'ylamine, N-isopropyl-N-propargylamine, N-allyl-N-propargylamine, N-butenyl-N-propargylamine, N-propargyl-N-propargylamine, N-cyclopropyl-N-propargylamine, N-methyl-N-ethinylamine and N-methyl-N-butinylarnine.

Conversion of the N'-cyclopropylglycinamides to the ethylenediamines of this invention having the formula (XXVIII) e wherein R, R R R 11 and Y are as represented above, is accomplished by the reduction of the appropriate glycinamide, for example, with lithium aluminum hydride. This reduction is preferably carried out in a solvent such ethyl ether, tetrahydrofuran, 1,2-dimethoxyethane or a polyglycol ether such as diglyme. Sodium borohydride may be employed in the presence of aluminum chloride using diethyleneglycol dimethyl ether as a solvent for the reduction.

Representative of the cyclopropylethylenediamines of this invention which may be produced in the foregoing manner are,

N-phenyl-N'-cyclopropylethylenediamine, N-phenyl-N-methyl-N'-cyclopropylethylenediamine, N-phenyl-N-propargyl-N'-cyclopropylethylenediamine, N-phenyl-N-benzyl-N'-cyclopropylethylenediamine, N-(m-trifiuoromethylphenyl -N-cyclopropyl-N'- cyclopropyl-N-methylethylenediamine, N-(p-chlorophenyl)-N-propargyl-N'-(2-phenylcyclopropyl)-N'-propargylethylenediamine, N-(p-ethoxyphenyl)-N-cinnamyl-N'-(Z-methylcyclopropyl)-N' 6-phenethylethylenediamine, N-benzyl-N'-cyclopropylethylenediamine, N-benzyl-N-methyl-N'-cyclopropylethylenediamine, N-benzyl-N-allyl-N'-cyclopropylethylenediamine, N-benzyl-N-propargyl-N'-cyclopropylethylenediamine, N-benzyl-N-cyclopropyl-N'-cyclopropy1ethylenediamine, N-benzyl-N-cyclopropylmethyl-N-cyclopropylethylenedia'mine, N-o-chlorobenzyl-N-methyl-N'-cyclopropylethylenediamine, N-m-trifluoromethyl-N-methy1-N'-cyclopropyl-N'- propargylethylenediamine, N-p-ethoxybenzyl-N-methyl-N'-cyclopropyl-N'- methylethylenediamine,

9 N-o-methylmercaptobenzyl-N-methyl-N'-cyclopropyl- N'-propargylethylenediamine, N-p-phenoxybenzyl-N-methyl-N'-cyclopropyl-N flphenethylethylenediamine, N-p-phenylbenzyl-N-allyl-N'-2-rnethy1cyclopropyl-N'- cinnamylethylenediamine, N-benzyl-N-methyl-N-2-phenylcyclopropylethylenediarnine, N-benzyl-N-methyl-N-2 (rn-trifiuoromethylphenyl) cyclopropylethylenediamine, N-benzyl-N-methyl-N'-2- (o-chlorophenyl) cyclopropylethylenediamine, N-benzyl-N-methyl-N-2-phenylcyclopropyl-N'-methyl ethylene-diamine, N-ben zyl N-methyl-N'-2-phenylcyclopropyl-N'-propargyl-ethylenediamine, N-benzyl-N-methyi-N'-cyclopropyl-N'-cinnamylethylenediamine, N-benzyl-N-methyl-N',N-bis-cyclopropylethylenediamine, N- 4-diethylsulfamylbenzyl) -N-methyl-N'-cyclopropylethylenediamine, N-cinnamyl-N-methyl-N'-cyclopropylethylenediamine, N-a-methylphenethyl-N-methyl-N'-cyclopropylethylenediamine, N-a-methyl-[i-phenoXyethyl-N-methyl-N cyclopropylethylenedi-amine, N-methyl-N-propargyl-N'-benzyl-N-cyclopropylethylenediamine, N-methyl-N-propargyl-N-benzyl-N'fi-methylcyclopropylethylenediamine, N-methyl-N-propargyl-N-benzyl-N-fi-allylcyclpropylethylenediamine, N-methyl-N-propargyl-N'-benzyl-N-fi-phenylcyclopropylethylenediamine, N-methyl-N-propargyl-N'-phenyl-N-cyclopropylethylenediamine, N-ethyl-N-propargyl-N'-benzyl-N-cyclopropylethylenediamine, N-isopropyl-N-propargyl-N'-benZyl-N'-cyc1opropylethylenediamine, N-allyl-N propargyl-N'-benzyl-N-cyclopropylethylenediamine, N-butenyl-N-propargyl-N-benzyl-N-cyclopropylethylenediamine, N-propargyl-N-propargyl-N'-benzyl-N'-cyclopropylethylenediamine, N-cyclopropyl-N-propargyl-N-benzyl-N'-cyclopropylethylene-di-amine, N-methyl-N-butinyl-N'-benzyl-N-cyclopropylethylenediamine, N-methyl-N-ethinyl-N'-benzyl-N-cyclopropylethylenediamine, N-propargyl-N-cyclopropylethylenediamine, N-propargylN'-benzyl-N'-cyclopropylethylenediamine and Namethyl-N-propargyl-N-cyclopropylethylenediatmine The tertiary cyclopropylethylenediamines of Formula XXVIII but wherein R is other than hydrogen, may also be produced by reacting a secondary di-amine such as N- benzyl-N-methyl N cyclopropylethylenediamine with a reactive alkyl, alkenyl, alkynyl, aralkyl, aralkenyl or aralkynyl halide in the presence of an acid acceptor such as triethylamine, potassium carbonate and an inert solvent such as benzene or toluene; and then methylating the secondary amine with formaldehyde and formic acid.

The tertiary ethylenediamines of this invention may also be produced by reacting a secondary diamine such as N- methyl-N'-benzyl-N'-cyclopropylethylenediamine with a Grignard reagent such as methylmagnesium bromide and allowing the resulting magnesium amide salt to interact with a reactive halide such as propargyl bromide. This method may be carried out according to the following reaction scheme:

An alternate process of forming the diamines of Formula I consists of forming an u-haloacetamide of the formula (XXIX) wherein R, Y, n, R R and R are as represented above. The glycinamide of Formula XXX may then be reduced with lithium aluminum hydride or sodium borohydride to the desired ethylenediamine of Formula I.

The starting materials used in the processes described herein are compounds which are either commercially available, Well-known in the art, or easily prepared in ac cor-dance with standard organic procedures previously described in the chemical literature.

For example, the preparation of various cyclopropylamines is described in J. Med. Pharm. Chem., 5(6), 1243- 1265, (1962), United States Patent Nos. 3,079,403, 3,081,336 and 3,083,226; British Patent No. 913,898; and Canadian Patent 'No. 685,776, etc.; and the preparation of various propangylamines is described in J. Med. Chem. 7, 390 (1964).

The compounds of this invention may be administered as the free bases or in the form of their nontoxic addition salts. They may be compounded and formulated into pharmaceutical preparations in unit dosage form for oral or parenteral administration with organic or inorganic solid materials or liquids which are pharmaceutically acceptable carriers. The compositions may take the form of tablets, powder granules, capsules, suspensions, solutions and the like. Such compositions are considered within the scope of this invention.

The compositions of this invention when administered orally or p-arenterally, in an effective amount, are effective in the treatment of depression and for monoamine oxidase 1 1 inhibition. The usual dosage is from 10 to 200 mgrn./kg., although lesser or greater quantities may be used.

The following examples are intended to illustrate the invention described herein without unduly restricting it.

EXAMPLE 1 Preparation of N '-cyclopr0pyl ot-chloroacetamide i Cyclopropylamine (70 gm., 1.23 mol) was added to 150 ml. water and cooled in an ice-water bath. To the stirred mixture was added dropwise and simultaneously 113 gm. (1.23 mol) a-chloroacetyl chloride and an aqueous solution containing 50 gm. of sodium hydroxide. The amide separated as a white solid and was collected by filtration. The solid was taken up in methylene chloride and dried with Na SO Removal of the solvent yielded 131 gm. of N'-cyclopropyl a-chloroacetamide having a melting point of til-84 C., and an ultraviolet absorption spectrum as follows:

xgfi f 2.96, 6.03, 6.65,.

EXAMPLE 2 Preparation of N -benzyl-N -cyclpropyl a-chloroacelamide A mixture of 29 gm. (0.2 mol) of N-benzyl-N'-cyclopropylamine and 65 ml. of water was cooled in an ice bath with good stirring. a-Chloroacetyl chloride (34 gm., 0.3 mol), and 8 gm. (0.2 mol) of NaOH in an equal volume of water were added simultaneously and dropwise to the cold amine solution. When the addition was completed, stirring was continued for another 30 minutes and the solution was extracted with ether. The ethereal solution was washed twice with 10% NaOH, then water, dried with MgSO and filtered. Removal of the ether in vacuo yielded a residue which was fractionally distilled. Yield 25 gm., B.P. 128-130/0.15 mm. Hg. Film/max. 3.08 and 6.08.

EXAMPLE 3 Preparation of N'-2-pheny lcycl0propyl u-chloroacetwmide 2-phenylcyclopropylamine (1.23 mol) was added to 150 ml. water and cooled in an ice-water bath. To the stirred mixture was added dropwise and simultaneously 113 gm. (1.23 mol) oz-ChlOl'OZlCCEYl chloride and an aqueous solution containing 50 gm. of sodium hydroxide. The amide separated as a white solid and was collected by filtration. The solid was taken up in methylene chloride and dried with Na SO Removal of the solvent yielded N'-2-phenylcyclopropyl tx-chloroacetamide.

EXAMPLE 4 When, in the procedure of Example 1, the cyclopropylamine is replaced by an equal molar amount of 2-methylcyclopropylamine, Z-ethylcyclopropylamine, 2-isopropylcyclopropylamine, 2-phenylcyclopropylamine,

2- benzylcyclopropylamine,

12 2-4-chlorophenylcyclopropylamine, 2-4-trifluoromethylphenylcyclopropylaminc, 2-4-methylphenylcyclopropylamine, 2-2-fiuorophenylcyclopropylamine, 2-3-methylphenylcyclopropylamine, 2-3-bromophenylcyclopropylamine, 2-2,6-dichlorophenylcyclopropylamine, 2-4-rnethylthiophenylcyclopropylamine, 2-2-dimethylsulfamylphenylcyclopropylamine, 2-2-iOdo-4-methylphenylcyclopropylamine, 2-4-isopropylphenylcyclopropylamine, 2-4-phenylphenylcyclopropylamine, 2-3-phenoxyphenylcyclopropylamine, 2-4-benzylphenylcyclopropylamine, 2-3,4-methylenedioxyphenylcyclopropylamine, 2-4-tluorophenylcyclopropylamine, 2-4-ch1orobenzylphenylcyclopropylamine, 2-phenethylcyclopropylamine, 2-allylcyclopropylamine, 2-propargylcyclopropylamine, 2-1-butinylcyclopropylamine, 2-ethinylcyclopropylamine, 2-ethenylcyclopropylamine, 2-1-propenylcyclopropylamine, 2-3-butenylcyclopropylamine, 2-1-hexenylcyclopropylamine, 2-phenylisopropylcyclopropylamine, 2-4-phenoxyphenylcyclopropylamine, 2-cinnamylcyclopropylamine, 2-2,4-dimethylphenylcyclopropylamine and 2-4-trifiuoromethylcinnamylcyclopropylamine, there are obtained,

N-2-methy1cycl0propyl a-chloroacetamide, N'-2-ethylcyclopropyl a-chloroacetamide, N'-2-isopropycyclopropyl a-chloroacetamide, N'-2-phenylcyclopropyl u-chloroacetamide, N'-2-benzylcyclopropyl u-chloroacetamide, N-2-4-chlor0phenylcyclopropyl a-choroacetamide, N-2-4-trifiuoromethylphenylcyclopropyl xchoroacetamide, N-2-4-methylphenylcyclopropyl ot-chloroacetamide, N-2-2-fluorophenylcyclopropyl ot-choroacetamide, N'-2-3-methylphenylcyclopropyl u-chloroacetamide, N-2-3-bromophenylcyclopropyl a-chloroacetamide,

N'-2-2,6-dichorophenylcyclopropyl ot-chloroacetamide,

N'-2-4-methylthiophenylcyclopropyl wchoroacetamide, N-2-2-dimethylsulfamylphenylcyclopropyl o.-

chloroacetamide, N'-2-2-iodo-4-methylphenylcyclopropyl occhloroacetamide, N-2-4-isopropylphenylcyclopropyl u-chloroacetamide, N'-2-4-phenylphenylcyclopropyl ot-chloroacetamide, N-2-3-phenoxyphenylcyclopropyl a-chloroacctamide, N'-2-4-benzylphenylcyclopropyl CL-ChlOl'OZiCtBtfll'IlldG, N-2-3,4-methylenedioxyphenylcyclopropyl achloroacetarnide, N'-2-4-fluorophenylcyclopropyl u-chloroacetamide, N-2-4-chlorobenzylphenylcyclopropyl a-chloroacetamide, N-2-phenethylcyclopropyl ot-chloroacetamide, N-2-allylcyclopr0pyl a-chloroacetamide, N'-2-propargylcyclopropyl a-chloroacetamide, N-2-l-butinylcyclopropyl a-chloroacetamide, N -2-ethinylcyclopropyl a-chloroacetarnide, N'-2-ethenylcyclopropyl tx-chloroacetamide, N'-2-l-propenylcyclopropyl a-chloroacetarnide, N'-2-3-butenylcyclopropyl a-chloroacetamide, N-2-l-hexenylcylopropyl ot-chloroacetamide, N'-2-phenylisopropylcyclopropyl a-chloroacetamide, N'-2-4-phenoxyphenylcyclopropyl a-chloroacetamide, N-2-cinnamylcyclopropyl a-chloroacetamide, N'-2-2,4-dimethylphenylcyclopropyl a-chloroacetamide and N-2-4-trifiuor0methylcinnamylcyclopropyl achloroacetamide, respectively.

1 3 EXAMPLE 5 When, in the procedure of Example 2, N'-benzyl-N- cyclopropylamine, is replaced by an equal molar amount of N-methyl-N-cyclopropylamine, N-isopropyl-N-cyclopropylamine, N-allyL-N-cyclopropylamine, N-propargyl-N-cyclopropylamine, N-phenethyl-N-cyclopropylamine, N-butyl-N'cyclopropylamine, N-ethinyl-N'-cyclopropylamine, Ncinnarnyl-N-cyclopropylamine, N'-l-butinyl-N-cyclopropylamine, N-1-propenyl-N-cyclopropylamine, N-methyl-N-2-phenylcyclopropylamine, N-methyl-N-2-(3-trifluoromethyl) phenylcyclopropylamine, N'-al1yl-N-2- (4-fiuoro phenylcyclopropylamine, N'-propargyl-N-2-( 3,4-methylenedioxy) phenylcyclopropylamine, N-benzyl-N-2- Z-methylthio phenylcyclopropylamine, N-methyl-N-2-benzylcyclopropylamine, N-methyl-N-2-(4-trifluoromethyl) phenylcyclopropylamine, N-benzyl-N-2-benzylcyclopropylamine, N-methyl-N'-2-2,6-dichlorophenylcyclopropylamine and N-methyl-N-2-2-methyl-4- trifiuoromethylphenylcyclopropylamine, there are obtained, N-methyl-N'-cyclopropyl a-chloroacetamide, N-isopropyl-N-cyclopropyl a-chloroacetamide, N'-allyl-N-cyclopropyl u-chloroacetamide, N-propargyl-N-cyclopropyl ot-chloroacetamide, N-phenethyl-N-cyclopropyl a-chloroacetamide, N-butyl-N-cyclopropyl wchloroacetamide, N-ethinyl-N-cyclopropyl a-chloroacetarnide, N'-cinnamyl-N'-cyclopropyl a-chloroacetamide, N-1-butinyl-N-cyclopropyl a-chloroacetamide, N'-1-propenyl-N-cyclopropyl a-chloroacetamide, N'-methyl-N-2-phenylcyclopropyl a-chloroacetamide, N'-methyl-N'-2-3-trifluoromethylphenylcyclopropyl achloroacetamide, N-allyl-N-2-4-fluorophenylcyclopropyl u-chloroacetarnide, N-propargyl-N'-2-3,4-methylenedioxyphenylcyclopropyl a-chloroacetamide, N'-benzyl-N'-2-2-methylthiophenylcyclopropyl qchloroacetamide, N'-m-ethyl-N-2-benzylcyclopropyl a-chloroacetamide, N-methyl-N'-2-4-trifluoromethylphenylcyclopropyl chloroacetamide, N-benzyl-N-2-benzylcyclopropyl a-chloroacetamide, N-methyl-N'-2-2,6-dichlorophenylcyclopropyl w chloroacetamide, and N-methyl-N-2-2-methyl-4- trifluoromethylphenylcyclopropyl a-chloroacetamide, respectively.

EXAMPLE 6 Preparation of a-(N-benzyl-N-methyl) -amin0-N- cyclopropylacetamide To a gently refluxing solution of a-chloro-N'-cyclopropylacetamide (131 g., 0.97 mol) and triethylamine (110 g.) in benzene (2 liters) was added dropwise N-methylbenzylamine (130 g., 1.0 mol). The solution was refluxed overnight, and upon cooling, the salts were removed by filtration. Benzene was removed in vacuo to leave a residue of 226 g. of crude oz- (N-benzyl-N-methyl) amino-N-cyclopropylacetamide.

14 A portion of the crude product was purified by distillation, B.P. C./ 0.2 mm. On standing, the a-(N-benzyl- N-methyl)amino N cyclopropylacetamide crystallized, and after washing with petroleum ether, showed a melting point of 49-52 C., and ultraviolet absorption spectra as follows:

x2e. 3.06, 6.02 6.55, 13.50 and 14.40,.

3 3.07, 6.03, 6.50, 13.50 and 14.40,. EXAMPLE 7 Preparation of N -benzyl-N -methyl-N cyclopropylethylenediamine a-(N-benzyl N methyl)amino N cyclopropylacetamide, prepared in Example 6, was dissolved in tetrahydrofuran (anhydrous) and added dropwise to a suspension of lithium aluminum hydride (43 g.) in anhydrous tetrahydrofuran (1 liter). After completion of the addition, the mixture was refluxed with stirring for 3 hours to complete the reduction. The mixture was cooled in an ice bath and the excess lithium aluminum hydride was destroyed by the addition of a saturated aqueous sodium sulfate solution. Upon removal of the tetrahydrofuran in vacuo, an oil remained which was dissolved in ether, dried over anhydrous potassium carbonate and purified by fractional distillation, B.P. 7072 C./0.100.15 mm., to yield 167 g. of N-benzyl-N-methyl-N-cyclopropylethylenediamine.

EXAMPLE 8 Preparation of N-benzyl-N-methyl-N'-cyclopr0pylethylenediamine dihydrochloride EXAMPLE 9 Preparation of N -benzyl-N -methyl-N '-cycl0pr0pyl- N'-f0'rmylelhylenediam ine a -w-Q To a chloroform solution containing N-benzyl-N-methyl N cyclopropylethylenediamine (8.0 g., 0.022 mol) prepared in Example 7, was added chloral (5.3 g.). The mixture was stirred at room temperature for 2 hours, and then refluxed for 1 hour. The chloroform was removed by distillation, and 8.9 g. of the product, N-benzyl-N- methyl-N'-cyclopropyl N formylethylenediamine, was collected by fractional distillation, B.P. 126-130 C./0.2

mm., had an ultraviolet absorption spectrum as follows:

A213, 6.00, 13.60 and 14.40;:

EXAMPLE 10 Preparation of N-benzyl-N'-cyclopropyl-N,N'-dimethylethylenea'zamine CH3 CH3 N-benzyl N methyl N cyclopropyl N formylethylenediamine, prepared in Example 9, was dissolved in tetrahydrofuran (anhydrous) and added dropwise to a suspension of lithium aluminum hydride (3.5 gm.) in

anhydrous tetrahydrofuran (1 liter). After completion of the addition, the mixture was refluxed with stirring for 3 hours to complete the reduction. The mixture was cooled in an ice bath and the excess lithium aluminum hydroxide was destroyed by the addition of a saturated aqueous sodium sulfate solution. Upon removal of the tetrahydrofuran in vacuo, 5.2 gm. of the product, N- benzyl N cyclopropyl-N,N-dimethylethylenediamine, were collected by distillation, B.P. 95100 C./0.2 mm., having an ultraviolet absorption spectrum as follows:

R213 110 band at 6.00, band at 13.65 and 14.40 a This indicates complete reduction of the formyl group.

EXAMPLE 11 Preparation of N-benzyl-N'-cyclopropyl-N,N'-dimethylethylenediamine dihydrochloride N benzyl N cyclopropyl N,N dimethylethylenediamine, prepared in Example 10, was converted to the dihydrochloride salt with gaseous HCl in ethanol, yielding 4.8 gm. of N-benzyl-N-cyclopropyl-N,N-dimethylethylenediamine dihydrochloride, which had a melting point of 117119 C.

EXAMPLE 12 Preparation of N-benzyl-N-methyl-N-cyclopropyl-N'- propargylethylenediamine To a refluxing solution (under nitrogen) of N-benzyl- N-methyl-N'-cyclopropyl-1,2-diaminoethane (12.7 gm., 0.062 mol) in tetrahydrofuran (100 ml.) were added dropwise 32.6 ml. of 2 N CH MgBr solution. After evolution of methane ceased, 7.4 gm. (0.062 mol) of propargyl bromide in benzene (150 ml.) were added to the reaction mixture and refluxed for 3 hours. The solution was treated with water (100 ml.), the benzene layer was decanted, and the aqueous part was extracted twice with benzene. After drying, the benzene was removed and the residue distilled. Material with a B.P. of 95100 C./0.15 mm., was collected, yielding 5.2 gm. of N-benzyl-N- methyl N cyclopropyl N propargylethylenediamine which had an ultraviolet spectrum as follows:

x33", 3.05, 13.75 and 14.40 a

EXAMPLE 13 Preparation of N-benzyl-N-methyl-N'-cycl0pr0pyl-N'- propargylethylenediamine dihydrochloride N-benzyl-N-methyl N cyclopropyl N propargylethylenediamine, prepared in Example 12, was converted to the dihydrochloride salt with gaseous HCl in ethanol.

Removal of ethanol yielded a gum which crystallized A213 3.05, 13.45, 14.35, 14.80 and 15.70 a

EXAMPLE 14 Preparation of a-(N-benzyl-N-methyl)amino-N'-2-phenylcyclopropylacetamide To a gently refluxing solution of 21.2 gm. (0.10 mol) of a-chloro-N'-2-phenylcyclopropylacetamide and 11.0 gm. triethylamine in 250 cc. of benzene were added drop- 16 wise 14.3 gm. (0.11 mol) of N-benZyl-N-methylamine and the solution refiuxed for 20 hours. After removal of the salts and the benzene, the product, a-(N-benzyl-N- methyl)amino-N'-2-phenylcyclopropylacetamide, was subjected to reduction without further purification as shown in the subsequent example.

EXAMPLE 15 Preparation of N-benzyl-N-methyl-N-2-phenylcyclopropylethylenediamine a (N benzyl N methyl)amino N 2 phenylcyclopropylacetamide, prepared in Example 14, was dissolved in tetrahydrofuran (anhydrous) and added dropwise to a suspension of lithium aluminum hydride (43 gm.) and anhydrous tetrahydrofuran (1 liter). After completion of the addition, the mixture was refluxed with stirring for 3 hours to complete the reduction. The mixture was cooled in an ice bath and the excess lithium aluminum hydride was destroyed by the addition of a saturated aqueous sodium sulfate solution. Upon removal of the tetrahydrofuran in vacuo, an oil remained which was dissolved in ether, dried over anhydrous potassium carbonate and purified by fractional distillation, B.P. 118 C./0.10 mm., to yield 15 gm., of N-benzyl-N- methyl-N-2-phenylcyclopropylethylenediamine.

EXAMPLE 16 Preparation of a-(N-m-trifluoromethylbenzyl- N-methyl)amin0-N'-cycl0propylacetamizle CH; a

a-chloro-N'-cyclopropylacetamide is reacted with N-mtrifluoromethylbenzyl-N-methylamine (obtained from the reaction of m-chloromethylbenzotrifluoride and excess methylamine) in the manner described in Example 6, to produce a-(N-m-trifiuoromethyl-benzyl-N-methyl)amino- N'-cyclopropylacetamide.

EXAMPLE 17 Preparation of N-m-Triflaoromezhylbenzyl-N-methyl- N -cycl0propyIetlzylenediamine 11 Q0 Bla r-o H20 rn-N- on. or.

Preparation of a-(N -o-chlorobenzyl-N-methyl am ino- N-cycl0propylacetamide CH: Cl

a-Chloro-N-cyclopropylacetamide is reacted with N-ochlorobenzyl-N-methylamine in the manner described in Example 6. The product, a-(N-o-chlorobenzyl-N-methyl) amino-N'-cyclopropylacetamide, is reduced without further purification as shown in the subsequent example.

25 and N-methylbenzylamine is replaced by an equal molar amount of N-methyl-N-propargylamine, N-ethinyl-N-propargylamine, N-isopropyl-N-propargylamine, N-allyl-N-propargylamine, N-butenyl-N-propargylamine, N-propargyl-N-propargylamine, N-cyclopropyl-N-propargylamine, N-methyl-N-ethinylamine and N-methyl-N-butinylamine,

there are obtained,

a-N-methyl-N-propargylarnino-N'-benzyl-N'- cyclopropylacetamide, a-N-ethinyl-N-propargylamino-N-benzyl-N- cyclopropylacetamide, m-N-isopropyl-N-propargylamino-N'-benzyl-N- cyclopropylacetamide, ot-N-allyl-N-propargylamino-N-benzyl-N'- cyclopropylacetamide, u-N-butenyl-N-propargylamino-N'-benzyl-N- cyclopropylacetamide, a-N-propargyl-N-propargylamino-N-benzyl-N'- cyclopropylacetamide, a-N-cyclopropyl-N-propargylamino-N-benzyl-N'- cyclopropylacetamide, a-N-methyl-N-ethinylamino-N-benzyl-N'- cyclopropylacetamide and wN-methyl-N-butinylamino-N'-benzyl-N'- cyclopropylacetamide, respectively,

EXAMPLE 27 When, in the procedure of Example 7, a-( N-benzyl-N- methyl)amino-N'-cyclopropylacetamide is replacedby an equal molar amount of each of'the products of Example 26, there are obtained,

EXAMPLE 28 Preparation of a-(N-cyclopropyl-N-benzyl)amino- N'-methylacetamide CH CH2 A benzene solution of a-chloro-N-methylacetamide (18.3 gm., 0.17 mol) was added dropwise to a refluxing mixture of N-cyclopropyl-N-benzylamine (25 gm., 0.17 mol) and 17.2 gm. of triethylamine in benzene and the reaction was allowed to proceed overnight. The solution was cooled, triethylamine-HCI was removed by filtration and the solution was concentrated in vacuo to yield 36.7

26 gm. of a residue. A portion of the crude amide, 3.0 gm., was distilled to give a-(N-cyclopropyl-N-benzyl)amino- N-methylacetamide, B.P. 147l53/0.07 mm. Hg.

Yield, 2.4 gm. igggq 2.95, 6.03, 6.52,.

EXAMPLE 29 N-methyl-N'-benzyl-N'-cyclopropylelhylenediamine a (N cyclopropyl N-benzyl)amino-N'-methylacetamide, 33.7 gm., was reduced with 10 gm. lithium aluminum hydride in tetrahydrofuran by refluxing overnight. Excess lithium aluminum hydride was destroyed with saturated Na SO solution and the tetrahydrofuran was removed by distillation at atmospheric pressure. The residue was distilled to yield a liquid, N-methyl-N-benzy1- N-cyclopropylethylenediamine, B.P. 127-1295 /6 mm.;

Yield, 32.2 gm. 7x11}; NoC=O A dihydrochloride was prepared with 6.0 gm. of the diamine from ethanolic HCl. Removal of solvent gave a gum which was crystallized from ethanol-ether. The solid was recrystallized from ethanol-ether and dried in a dessicator. Yield, 5.5 gm. of N-methyl-N'-benzyl-N-cyclopropylethylenediamine dihydrochloride, M.P. 145148 C.

Analysis.-Calcd for C H N Cl C, 56.36%; H, 8.01%; N, 10.11%; Cl, 25.60%. Found: C, 56.16%; H, 8.04%; N, 10.26%; Cl, 25.80%.

EXAMPLE 30 Preparation of N-methyl-N-pr0pargyl-N-benzyl-N'- cyclopropylethylenediamine To a refluxing solution of N methyl N benzyl N'- cyclo propylethylenediamine, 13.8 gm. (0.06 mol) in tetrahydrofuran was added 33 ml. of 2 N CH MgBr. When evolution of gas ceased, 7.2 gm. of propargyl bromide in ml. of dry benzene was added dropwise. After 3 hours refluxing, the solution was cooled, 100 ml. water was added, and the benzene layer was decanted. The water layer was again extracted twice more With benzene and the benzene extracts were dried and made free of solvent. An oil, 16.7 gm., was obtained which was distilled to yield 8.0 gm. of N methyl N propargyl- N benzyl N cyclopropylethylenediamine; RP. 99- 114/0.09 mm.

max.

A crystalline dihydrochloride was obtained from ethanol ether and recrystallized from the same solvent system to yield 5.4 gm. of N methyl N propargyl N'- benzyl N cyclopropylethylenediamine dihydrochloride; M.P. 171-174 C. with decomposition.

Thus, it is apparent from the foregoing description that the objects of this invention have been attained. Novel compounds have been invented which have anti depressant activity and inhibit monoamine oxidase. In addition, a novel method of treating depression has been invented.

While this invention has been described and exemplified in terms of its preferred embodiment, those skilled in the art will appreciate that modifications can be made Without departing from the spirit and scope of this invention.

We claim: 1. A compound selected from the group consisting of compounds of the formula wherein R is a member selected from the group consisting of thienyl, pyridyl, naphthyl and Ph-, wherein Phis a radical of the formula wherein R and R are each a member selected from the group consisting of hydrogen, chloro, bromo, iodo, fluoro, trifiuoromethyl, (lower)alkyl, (lower) alkoxy, (lower)alkylthio, di(lower)alkylsulfamyl, phenyl, phenoxy, benzyl, and when taken together, methylenedioxy;

n is a whole integer from 0 to l inclusive;

R is a member selected from the group consisting of straight chain radicals selected from the group consisting of (lower)alkyl, (lower)alkenyl, (lower) alkynyl and cycloalkyl radicals having from 3 to 7 carbon atoms, inclusive:

R is a member selected from the group consisting of hydrogen and straight chain radicals selected from the group consisting of (lower)alkyl, (lower)alkenyl, (lower) alkynyl, phenylalkyl and phenylalkenyl wherein the alkyl and alkenyl moieties contain from 14 carbon atoms inclusive;

R is a member selected from the group consisting of hydrogen and straight chain radicals selected from the group consisting of (lower)alkyl, (lower)alkenyl, (lower)alkynyl, Pl1-, Ph-all(-, and Ph-alken-, in which P11 is as represented above, alk represents a divalent alkylene radical containing from 1 to 4 carbon atoms, inclusive, and alken represents a divalent alkenylene radical containing from 2 to 4 carbon atoms, inclusive; and

Y is a member selected from the group consisting of (lower)alkylene, (lower)alkenylene, (lower)alkynylene, oxy(lower)alkylene and mercapto(lower) alkylene;

and a pharmaceutically acceptable nontoxic salt thereof.

2. A compound of the formula wherein R is a member selected from the group consisting of hydrogen straight chain radicals selected from the group consisting of (lower)alkyl, (lower)alkenyl, (lower) alkynyl, Ph-, Ph-alk-, and Ph-alken-, wherewherein the alkyl and alkenyl moieties contain from 1-4 carbon atoms inclusive; and

R is a member selected from the group consisting of hydrogen straight chain radicals selected from the group consisting of (lower)alkyl, (lower)alkenyl, (lower)alkynyl, Ph-, Ph-alk-, and Ph-alken-, wherein alk represents a divalent alkylene radical containing from 1 to 4 carbon atoms, inclusive, alken represents a divalent alkenylene radical containing from 2 to 4 carbon atoms, inclusive, and Ph represents a radical of the formula wherein R and R are each a member selected from the group consisting of hydrogen, chloro, bromo, iodo, fluoro, trifiuoromethyl, (lower)alkyl, (lower) alkoxy, (lower) alklthio, di(lower)alkylsulfamyl, phenyl, phenoxy, benzyl, and when taken together, methylenedioxy.

3. A compound of the formula wherein R is a member selected from the group consisting of hydrogen straight chain radicals selected from the gnoup consisting of (lower)alkyl, (lower)alkenyl, (lower)alkynyl, phenylalkyl and phenyl alkenyl wherein the alkyl and alkenyl moieties contain from 1-4 carbon atoms inclusive; and

R is a member selected from the group consisting of wherein R and R are each a member selected from the group consisting 'of hydrogen, chloro, bromo, iodo, fluoro, trifiuoromethyl, (lower) alkyl, (lower) alkoxy, (lower)alkylthio, di(lower)alkylsulfarnyl, phenyl, phenoxy, benzyl, and when taken together, methylenedioxy.

4. A compound of the formula wherein R is a member selected from the group consisting of hydrogen, (lower)alkyl, (lower)alkenyl, (lower) alkynyl, phenylalkyl and phenylalkenyl; and

R is a member selected from the group consisting of hydrogen, (lower) alkyl, (lower)alkenyl, (lower-alkynyl, Ph-, Ph-'alk,- an-d Ph-a1ken-, wherein alk represents a divalent alkylene radical containing from 1 to 4 carbon atoms, inclusive, alken represents a divalent alkenylene radical containing from 2 to 4 carbon atoms, inclusive, and Ph represents a radical of the formula wherein R and R are each a member selected from the group consisting of hydrogen, chloro, bromo, iodo, fluoro, trifiuoromethy1, (lower) alkyl, (lower) alkoxy, (lower)alkylthio, di(lower)alkylsulfamy1, 'phenyl, phenoxy, benzyl, and when taken together, methylenedioxy.

29 5. A compound of the formula C HzlTTC H20 H2N R5 CH3 I l wherein R and R are each a member selected from the group consisting of hydrogen, chloro, bromo, iodo, fluoro, trifluoromethyl, (l-ower)-alkyl, (lower) alkoxy, (lower)alkylthio, -di(lower)a1kylsulfarnyl, phenyl, pherloxy, benzyl, and when taken together, methylenedioxy; and

R and R are as represented above.

6. The compound of the formula 7. A pharmaceutioally acceptable nontoxic salt of the compound of claim 6.

8. The compound of the formula 5 Q-cmqwomom- (1H, 9. The compound of the formula r @om-rr-omom-N 6H, 10. The compound of the formula 0F, -CH2NCHzCHiI% (1H, 11. The compound of the formula H @omag-cmcm-zcd 12. The compound of the formula 0 Fa'CHaN-C H,oHr-- 5 References Cited FOREIGN PATENTS 625,100 5/ 1963 Belgium.

JOHN D. RANDOLPH, Primary Examiner.

WALTER A. MODANCE, Examiner.

A. ROTMAN, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 ,365 ,458 January 23 1968 John H. Biel et a1 It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 4, line 65, "brain" should read brains Column 6, line 75, "2,927,180" should read 2,937,180 Column 8, line 43, "solvent such" should read solvent such as Column 13, line 19, "N-allylN-2-" should read Nally1-N 2- Column 15 line 5 "hydroxide" should read hydride line 9, "were collected" should read was collected lines 34, 37 and 75, "were added", each occurrence, should read was added Column 18, line 4, after "propylacetamide," insert a-N-benzylN-methylamino-N2-3- methylphenylcyclopropylacetamide, Column 20, line 6, cancel Nmethyl-N2,3-trifluoromethylphenylcyclopropyl". Column 21, line 23, "N-benbyl-N-methyl" should read N-benzylN-methyl- Column 23, line 20, "-Ncyclopropy1-" should read I N-cyclopropylacet- Column 27, line 66, "Ph, Phalk,

and Phalken-, where" should read phenylalkyl and phenylalkenyl Column 28, line 29, "groups consisting of" should read group c onsisting ofline 56 beginning with "hydrogen," cancel all to and including "formula" in line 65, same column 28 and insert hydrogen straight chain radicals selected from the group consisting of (lower)alkyl (lower)al1 enyl (lower) alkynyl, phenylalkyl and phenylalkenyl wherein the alkyl and alkenyl moities contain from 1 to 4 carbon atoms inclusive; and

R is a member selected from the group consisting of hydrogen straight chain radicals selected from the group consisting of (lower)alkyl, (lower)alkenyl, (lower)alkynyl, Ph, Ph-

alk-, and Ph-alken-, wherein alk represents a divalent alkylene radical containing from 1 to 4 carbon atoms, inclusive, alken represents a divalent alkenylene radical containing from 2 to 4 carbon atoms inclusive and Ph represents a radical of the formula Column 29 line 10, beginning with "hydrogen," cancel all to and including "formula" in line 19, same column 29, and insert hydrogen straight chain radicals selected from the group consisting of (lowerJalkyl (lower) alkenyl, (lowerjalkynyl, phenylalkyl, and phenylalkenyl wherein the alkyl and alkenyl moities contain from 1 to 4 carbon atoms inclusive; and R is a member selected from the group consisting of hydrogen straight chain radicals selected from the group consisting of (lowerjalkyl, (1ower)alkenyl, (lower)alkyl, Ph-, Ph-alk, and Ph-alken-, wherein alk represents a divalent alkylene radical containing from 1 to 4 carbon atoms, inclusive, alken represents a divalent alkenylene radical containing from Z to 4 carbon atoms, inclusive and Ph represents a radical of the formula Signed and sealed this 9th day of September 1969.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR.

Attesting Officer Commissioner of Patents 

